REGULATION OF ANTI-TUMOR IMMUNITY

描述(申请人提供)：“肿瘤免疫调节”课程汇集了微生物学和免疫学系、医学系血液和肿瘤科和病理学系的研究人员，共同努力解决紧迫的问题，使免疫疗法能够对患者的护理和治疗做出重要贡献。该计划的长期目标是找到通过抗肿瘤疫苗形式的免疫疗法治疗肿瘤的方法。为了开发成功的免疫疗法，有必要确定允许产生抗肿瘤免疫并允许在较长时间内维持抗肿瘤效应功能的参数。随着时间的推移，维持抗肿瘤效应反应需要我们理解记忆的形成和维持。该计划在几个项目中的一个重要目标是阐明在已建立的肿瘤存在的情况下能够产生和维持记忆的分子机制。抗肿瘤免疫需要TH1免疫反应的极化。在TH2和TH1极化相互拮抗的程度上，我们认为消除TH2反应可能有利于抗肿瘤治疗。B细胞是TH2极化的最终效应者，我们已经证明，消除它们可以增加抗肿瘤活性。因此，在几个项目中检查的该计划的第二个目标是分析在没有B细胞的情况下抗肿瘤免疫的机制。这些研究还旨在发现B细胞抑制抗肿瘤TH1反应的分子途径。我们自己的研究和其他人的研究都支持这样的假设，即先天免疫反应的激活对于产生强大的适应性反应和记忆的产生是重要的。因此，该计划在三个项目中追求的第三个目标是分析NK细胞和DC在抗肿瘤免疫中的作用。由于我们已经证明了由肿瘤细胞分泌的热休克蛋白可以激活DC、NK和CD8CTL，这种激活模式将在所有项目中进行研究，并检测自体骨髓移植中记忆的形成、免疫的产生以及在B细胞耗尽条件下的影响。最后，基于热休克蛋白的疫苗将被用来检验非免疫原性肿瘤是基于疫苗的免疫治疗的最佳靶点的假设。第一阶段/第二阶段试验 非小细胞肺癌患者将检查免疫反应的产生和临床益处。

DESCRIPTION (provided by applicant): The Program on "Regulation of Tumor Immunity" brings together investigators from the Department of Microbiology and Immunology, the Division of Hematology and Oncology in the Department of Medicine and the Department of Pathology to work together on the pressing problem of bringing Immunotherapy to a point where it can make an important contribution to patient care and treatment. The long-range goal of the program is to find ways to treat tumors with the aid of immunotherapy in the form of anti tumor vaccines. In order to develop successful immunotherapy it is necessary to define the parameters that allow the generation of anti tumor immunity and allow the maintenance of anti tumor effector functions over prolonged periods of time. Maintaining anti tumor effector responses over time necessitates our understanding of memory formation and maintenance. One important goal of the program in several projects is the elucidation of molecular mechanisms able to generate and maintain memory in the presence of established tumors. Anti tumor immunity requires TH1 polarization of the immune response. To the extent that TH2 and TH1 polarization are mutually antagonistic we suggest that elimination of TH2 responses may be beneficial for anti tumor therapy. B cells are the final effectors of TH2 polarization and we have shown that their elimination allows increased anti tumor activity. A second goal of the program examined in several projects therefore is the analysis of the mechanisms of anti tumor immunity in the absence of B cells. These studies are also aimed at the discovery of molecular pathways by which B cells dampen the anti tumor TH1 response. Our own studies and those by others support the hypothesis that the activation of the innate immune response is important for the generation of a powerful adaptive response and the generation of memory. The third goal of the program pursued in three projects therefore is the analysis of the contribution of NK cells and DC to anti tumor immunity. Since we have shown that heat shock proteins secreted by tumor cells activate DC, NK and CD8 CTL this mode of activation will be studied in all projects and examined with regard to memory formation, generation of immunity in autologous bone marrow transplantation and in its effects under conditions of B cell depletion. Finally, a heat shock protein based vaccine will be used to test the hypothesis that non-immunogenic tumors are the best targets for vaccine-based immunotherapy. A phase I/II trial for non-small cell lung carcinoma patients will examine generation of an immune response and clinical benefit.